Title | Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Di Vizio D, Adam RM, Kim J, Kim R, Sotgia F, Williams T, Demichelis F, Solomon KR, Loda M, Rubin MA, Lisanti MP, Freeman MR |
Journal | Cell Cycle |
Volume | 7 |
Issue | 14 |
Pagination | 2257-67 |
Date Published | 2008 Jul 15 |
ISSN | 1551-4005 |
Keywords | Animals, Caveolin 1, Cell Line, Tumor, Enzyme Activation, Fatty Acid Synthases, Humans, Male, Membrane Microdomains, Mice, Mutation, Palmitic Acid, Phosphoinositide-3 Kinase Inhibitors, Prostate, Prostatic Neoplasms, Protein Binding, Protein Kinase Inhibitors, Protein Transport, Proto-Oncogene Proteins pp60(c-src), Signal Transduction |
Abstract | Fatty Acid Synthase (FASN), a cytoplasmic biosynthetic enzyme, is the major source of long-chain fatty acids, particularly palmitate. Caveolin-1 (Cav-1) is a palmitoylated lipid raft protein that plays a key role in signal transduction and cholesterol transport. Both proteins have been implicated in prostate cancer (PCa) progression, and Cav-1 regulates FASN expression in a mouse model of aggressive PCa. We demonstrate that FASN and Cav-1 are coordinately upregulated in human prostate tumors in a hormone-insensitive manner. Levels of FASN and Cav-1 protein expression discriminated between localized and metastatic cancers, and the two proteins exhibited analogous subcellular locations in a tumor subset. Endogenous FASN and Cav-1 were reciprocally co-immunoprecipitated from human and murine PCa cells, indicating that FASN forms a complex with Cav-1. FASN, a cytoplasmic enzyme, was induced to associate transiently with lipid raft membranes following alterations in signal transduction within the Src, Akt and EGFR pathways, suggesting that co-localization of FASN and Cav-1 is dependent on activation of upstream signaling mediators. A Cav-1 palmitoylation mutant, Cav-1(C133/143/156S), that prevents phosphorylation by Src, did not interact with FASN. When overexpressed in Cav-1-negative PCa cells, Cav-1(C133/143/156S) caused a reduction of both Src and Akt levels, as well as of their active, phosphorylated forms, in comparison with wild type Cav-1. These findings suggest that FASN and Cav-1 physically and functionally interact in PCa cells. They also imply that palmitoylation within this complex is involved in tumor growth and survival. |
DOI | 10.4161/cc.7.14.6475 |
Alternate Journal | Cell Cycle |
PubMed ID | 18635971 |
Grant List | P50 DK65298 / DK / NIDDK NIH HHS / United States R01 CA101046 / CA / NCI NIH HHS / United States R01 CA112303 / CA / NCI NIH HHS / United States R3747556, / / PHS HHS / United States |
Related Faculty:
Massimo Loda, M.D.